Through dedicated research into biomarker discovery and patient care, the neuroimmunology laboratory at Mayo Clinic has paved a new way of life for those with autoimmune disorders.
The care and management for patients with autoimmune disorders, specifically neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorder (NMOSD), were revolutionized less than 20 years ago when researchers at Mayo Clinic discovered a critical serum autoantibody biomarker, the NMO antibody (NMO-IgG).1 This antibody, and its target, the aquaporin-4 (AQP4) water channel, represented a breakthrough in the diagnosis and treatment for these disorders, which were plagued by high rates of misdiagnosis for years.
The discovery, led by Vanda A. Lennon, MD, PhD, an immunologist at Mayo Clinic in Rochester, Minnesota, improved the understanding of the immunopathological mechanisms underlying NMOSD and allowed for the development of novel therapies. The efforts by Lennon and her colleagues set a pathway for success that other Mayo Clinic researchers, including Sean J. Pittock, MD, have followed.
Pittock, the director of the Mayo Clinic Center for MS and Autoimmune Neurology, was a resident in Lennon’s lab at the time of the discovery. "If you want a story about the concept of biomarker discovery to near cure, the NMO story is an incredible one for rare disease," he told NeurologyLive®. "The NMO story at Mayo Clinic encompasses what the center is all about… We’re beginning to understand the immune pathology of these diseases and now we’re recognizing precision-targeted therapies."
Currently, part of Pittock’s time is spent directing the neuroimmunology laboratory and the autoimmune neurology clinic, which is the first of its kind specifically focused on people with autoimmune neurological diseases. Inside the lab, there are more than 100 workers, consisting of consultants, residents, fellows, technologists, technicians, research scientists, and many more. As the number of antibody biomarkers transitioning from the research setting into clinical laboratories has accelerated, so has the demand and complexity of panel-based testing, an area Pittock and his colleagues in the lab prides themselves on.
"If there’s an antibody biomarker that’s pertinent to that presentation—if you order tests from us, we will test for it,” he said. Given the limitations of neural antibody testing, not only does the laboratory evaluate standard analytical performance characteristics such as precision, accuracy, reportable range, reference range, and analytical specificity, but it incorporates a rigorous evaluation of diverse samples.2 To ensure that staff members who are interpreting tissue and cell-based immunofluorescence assays are able to correctly identify all reportable antibodies with high sensitivity and specificity, Mayo Clinic developed a robust 9-week training program. Furthermore, all positive cases are reviewed by a neurologist or a PhD-level laboratory director prior to reporting out results.
Those in the training program have access to the largest sample biobank of clinically defined patient serums/cerebrospinal fluid in the autoimmune field in the US. Clinically defined specimens from that biobank are utilized by those in the program, first in an unblinded fashion, and then subsequently in a blinded fashion. Following the 9-week program, individuals must pass a blinded competency examination, where they are asked to interpret a complex group of reportable neural antibodies. Even after they pass, Mayo Clinic maintains regular yearly evaluations of reader performance across all reportable antibodies.
"Nearly half of patients with autoimmune encephalitis do not have an antibody biomarker yet. ‘Yet’ being the main thing," Anastasia Zekeridou, MD, PhD, told NeurologyLive®. Zekeridou, a senior associate consultant at Mayo Clinic, spends half of her time in the neuroimmunology lab and the other half working in the autoimmune clinic. Her research interests include neural autoantibody biomarkers, paraneoplastic neurological syndromes, and neurological complications of immune-checkpoint inhibitor cancer immunotherapy.
Pittock and Zekeridou were both a part of a study that tested 42,032 patients in the neuroimmunology laboratory to determine the frequency of detection and age/sex associations of autoimmune/paraneoplastic encephalitis antibody biomarkers. Although uncommon, autoimmune/paraneoplastic encephalitis/encephalopathy is an increasingly recognized condition with several antibody biomarkers that have transformed diagnosis. Through the lab, the investigators were able to provide a unique big-picture perspective in examining these rare diseases, which are often difficult to study because of small sample sizes.3
The advancement of antibody biomarkers, specifically AQP4, has led to several notable therapeutic developments, some of which were led by researchers at Mayo. Pittock and his colleague Dean M. Wingerchuk, MD, an autoimmune neurologist at Mayo Clinic in Scottsdale, Arizona, were the primary investigators of one of the early studies of eculizumab (Soliris; Alexion Pharmaceuticals), a compliment C5 inhibitor.4 That study, which showed nearly complete cessation of disease activity, paved the way for a phase 3 trial that led to the drug’s FDA approval in 2019, making it the first approved medication for NMOSD.5
Pittock and Wingerchuk also served with Brian G. Weinshenker, MD, a neurologist at Mayo Clinic’s campus in Minnesota, on the steering committee of the clinical trial investigating inebilizumab (Uplizna; Horizon) for the treatment of NMOSD. In 2020, the FDA approved the Horizon therapeutic based on data from the phase 2/3 N-MOmentum study (NCT02200770), which showed that 88% of patients who received the therapy were relapse-free 28 weeks after starting treatment, compared with 61% in the placebo group.6
Eculizumab, inebilizumab, and satralizumab (Enspryng; Genentech) are the only FDA-approved medications for NMO. Other drugs used off-label to prevent attacks include rituximab (Rituxan; Genentech), mycophenolate mofetil (CellCept; Genentech), azathioprine (Imuran, Azasan; Prometheus), prednisone, and methotrexate. Most recently, Pittock was the primary investigator of the CHAMPION-NMOSD trial (NCT04201262), which showed that ravulizumab (Ultomiris; AstraZeneca), a long-acting C5 compliment inhibitor previously approved for adults with generalized myasthenia gravis, resulted in no clinical relapses in patients with AQP4 antibody positive NMOSD over a 73-week treatment period.7
"Now, we went from a disease that resulted in you being blind or wheelchair bound or dead in 5 years, to a disease that, with the new ravulizumab trial, has a 100% chance of stopping you from having a clinical attack of that devastating illness," Pittock said.
The neuroimmunology research laboratory discovers approximately 2 new antibody biomarkers of autoimmune or paraneoplastic neurological disorders a year, however the research does not stop there.8 "We try to refine our antibody biomarkers," Zekeridou said. “It’s not only the antibody discovery or biomarker discovery, but it’s also figuring out how useful they are. Then, what are the nuances in the diagnosis? Or how can we use this antibody in the future?
On top of the research being conducted, the neuroimmunology laboratory has adopted a new model of care Pittock calls the “Mayo Clinic 3-M” approach. The first M stands for “Maximize reversibility.” Here, patients are given large doses of immunotherapy over a short period of time, with maximum reversibility measured through phenotype-specific evaluations. Pittock gave several examples of patients, saying, “If you come in with epilepsy, we count your seizures, or we do epilepsy monitoring. We give you your therapy, we measure, and then we get a sense of that big treatment trial."
The second M is "Maintaining maximum reversibility." Once a patient has reached a point where they have shown progress with their treatment regimen, it becomes a question of maintainance because patients cannot be given steroids in perpetuity, Pittock explained. The next step is to select an immunotherapy that spares agents such like steroids and other choices like intravenous immunoglobulin, and use other drugs including rituximab, methotrexate, and in other cases, other drugs, suchn as IL-6 inhibitors like satralizumab.
The third M is "Minimum dose of immunotherapy" to lower risk of adverse effects while maintaining the maximum reversibility. Patients on immunotherapy may experience a range of these, from flu-like symptoms such as fever, chills, weakness, nausea or vomiting, fatigue, headache, or trouble breathing, to other adverse effects including swelling and weight gain, heart palpitations, diarrhea, organ inflammation, and infection.
"What do we still need to work on? We discussed biomarkers and the immunopathology, but we still need to work on the treatment part," Zekeridou said. "The NMO example is a perfect example, but the thing the NMO trials has taught us is that we cannot do it alone. These trials were multicentered around the world. We’re dealing with rare diseases, so we need this kind of collaboration. We also need to do a better job of advocating for our patients until we have FDA-approved drugs. This is something we see in our clinic every day, where patients will not get insurance for specific treatments, even though they do have autoimmune encephalitis."
Despite the immense progress from within the NMO field, the research has not slowed up. Although it requires several well-trained staff, “the process has allowed us to go from a rare, devastating disease to a disease that’s nearly cured in 20 years. That story is the poster child for rare, orphan diseases and how a community of talent and different specialties comes together to cure that disease. That’s a story that people will want to read,” Pittock said.